The potential role of amyloid β in the pathogenesis of age-related macular degeneration
Takeshi Yoshida, Kyoko Ohno-Matsui, Shizuko Ichinose, Tetsuji Sato, Nobuhisa Iwata, Takaomi C. Saido, Toshio Hisatomi, Manabu Mochizuki, Ikuo Morita
Takeshi Yoshida, Kyoko Ohno-Matsui, Shizuko Ichinose, Tetsuji Sato, Nobuhisa Iwata, Takaomi C. Saido, Toshio Hisatomi, Manabu Mochizuki, Ikuo Morita
View: Text | PDF
Research Article Angiogenesis

The potential role of amyloid β in the pathogenesis of age-related macular degeneration

Abstract

Drusen are extracellular deposits that lie beneath the retinal pigment epithelium (RPE) and are the earliest signs of age-related macular degeneration (AMD). Recent proteome analysis demonstrated that amyloid β (Aβ) deposition was specific to drusen from eyes with AMD. To work toward a molecular understanding of the development of AMD from drusen, we investigated the effect of Aβ on cultured human RPE cells as well as ocular findings in neprilysin gene–disrupted mice, which leads to an increased deposition Aβ. The results showed that Aβ treatment induced a marked increase in VEGF as well as a marked decrease in pigment epithelium-derived factor (PEDF). Conditioned media from Aβ-exposed RPE cells caused a dramatic increase in tubular formation by human umbilical vein endothelial cells. Light microscopy of senescent neprilysin gene–disrupted mice showed an increased number of degenerated RPE cells with vacuoles. Electron microscopy revealed basal laminar and linear deposits beneath the RPE layer, but we did not observe choroidal neovascularization (CNV). The present study demonstrates that Aβ accumulation affects the balance between VEGF and PEDF in the RPE, and an accumulation of Aβ reproduces features characteristic of human AMD, such as RPE atrophy and basal deposit formation. Some other factors, such as breakdown of integrity of Bruch membrane, might be necessary to induce CNV of AMD.

Authors

Takeshi Yoshida, Kyoko Ohno-Matsui, Shizuko Ichinose, Tetsuji Sato, Nobuhisa Iwata, Takaomi C. Saido, Toshio Hisatomi, Manabu Mochizuki, Ikuo Morita

×

Figure 8

Options: View larger image (or click on image) Download as PowerPoint
Localization of Aβ in sub-RPE deposits from neprilysin gene–disrupted mi...
Localization of Aβ in sub-RPE deposits from neprilysin gene–disrupted mice by indirect immunogold labeling. Cryostat sections were prepared from senescent neprilysin gene–disrupted mice and incubated with anti-Aβ antibody (4G8) and anti-mouse 10- to 15-nm gold conjugate (for scanning electron microscopy images) or 5- to 10-nm gold conjugate (for transmission electron microscopy images). Gold particles were present within the subretinal deposit (C and E) as well as in the cytoplasm of RPE cells (E, arrowheads). A–C are scanning electron microscopy images. B shows higher magnification of A, and C shows higher magnification of B. D and E are transmission electron microscopy images. E shows higher magnification of D. DE, subretinal deposit; BM, Bruch membrane; CH, choroid. Scale bars: 10 μm (A); 3.6 μm (B); 360 nm (C); 1 μm (D); and 0.1 μm (E).